Prognostic Implications of Left Ventricular Hypertrophy and Mechanical Function in Fabry Disease: A Longitudinal Cohort Study.

BACKGROUND: The prognostic value of different grades of left ventricular hypertrophy (LVH) and left ventricular (LV) mechanical function in Fabry disease is unclear. We aimed to evaluate the association between the severity of LVH, LV mechanical function, and clinical outcomes in Fabry disease. METHODS: We conducted a retrospective cohort study from a single-center registry of adult patients with Fabry disease. Left ventricular mass index (LVMI) was measured by echocardiography. The severity of LVH was categorized by LVMI using the sex-specific cutoff values. Left ventricular mechanical function was measured as LV global longitudinal strain (GLS) by speckle-tracking analysis. The primary outcome was a composite of major adverse cardiovascular events (MACE) at 5 years, including heart failure hospitalization, sustained ventricular tachycardia, acute ischemic stroke, and all-cause mortality. RESULTS: The study included 268 patients (age 50.4 ± 15.4 years, men 46.6%) with Fabry disease (83.2% IVS4+919G > A mutation), and 106 patients (39.6%) had LVH. Patients with mild, moderate, or severe LVH had 5-year MACE rates of 7.4%, 10%, and 30.5%, respectively (P < .001). Moreover, patients with impaired LV GLS (<14.1%) had a higher 5-year MACE rate than those with preserved LV GLS (32.1% vs 2.4%, P < .001). Severe LVH was an independent predictor of MACE compared with absence of LVH (adjusted hazard ratio, 12.73; 95% CI, 1.3-124.71; P = .03), after adjusting for age, sex, hypertension, hyperlipidemia, atrial fibrillation, renal function, average E/e', enzyme replacement therapy, and LV GLS. Patients with severe LVH and impaired LV GLS had the highest incidence for MACE (log-rank P < .05), irrespective of sex, genotypes, and whether receiving enzyme replacement therapy or not. CONCLUSIONS: Sex-specific grading of LVH by LVMI is practical for risk stratification in patients with Fabry disease, and impaired LV GLS further refines the prognostication.

Hepatotoxicity and Mutagenicity assessment during chronic in vivo exposure to aqueous extracts from Peperomia pellucida.

Studies on herbal medicine have exposed some toxic effects on humans. Peperomia pellucida (L.) HBK (P. pellucida) is one of the herbal medicines recommended as an alternative to synthetic medicine for diseases. Studies exist on the pharmacological activities of P. pellucida extracts, but studies on the potential hepatotoxic and mutagenic effects of subchronic administration of P. pellucida aqueous extracts, which is very important knowledge when we venture into alternative medicine, are lacking. In this study, two concentrations (60 mg/kg and 30 mg/kg) of P. pellucida aqueous extracts - decoction and freeze-dried extracts -were administered in vivo to BALB/c mice for nine (9) weeks. Significant differences were observed between the 60 mg/kg freeze-dried extract and the control in terms of mice weight and micronucleus frequency at 7-8 weeks of treatment. Also, no significant differences were found between groups in serum transaminases levels. Generally, there is no sufficient evidence to show that subchronic exposure to P. pellucida aqueous extracts is hepatotoxic though 60 mg/kg concentration may be mutagenic. This study suggests that although the herbal medicine is safe for prolonged consumption, users are advised to take precautions and moderations of its use due to the possibility of potential mutagenic effects.

Complex Valued Deep Neural Networks for Nonlinear System Modeling.

Deep learning models, such as convolutional neural networks (CNN), have been successfully applied in pattern recognition and system identification recent years. But for the cases of missing data and big noises, CNN does not work well for dynamic system modeling. In this paper, complex valued convolution neural network (CVCNN) is presented for modeling nonlinear systems with large uncertainties. Novel training methods are proposed for CVCNN. Comparisons with other classical neural networks are made to show the advantages of the proposed methods.

Ocular manifestations of multiple sclerosis in patients from three countries: A Web-based survey.

OBJECTIVE: This study evaluates the epidemiological characteristics, ophthalmological manifestations, and different therapeutic options available for patients with multiple sclerosis (MS) in China, Spain, and Cuba. METHODS: A self-designed questionnaire was used to conduct a comparable descriptive cross-sectional study on patients with MS. The survey included patients' demographic data, ocular manifestations related to MS, and treatment methodology followed in the three countries. The online survey was designed using the Wenjuanxing survey platform, and a survey link was circulated through WhatsApp, WeChat, and emails. Quantitative data were expressed as mean and standard deviation, the Kruskal-Wallis test was used for non-parametric variables. Qualitative data were expressed as numerical and percentage. The chi-square test (χ2) was used to compare the group's response categories. The statistical difference was considered significant when p < 0.05. RESULTS: The female-to-male ratio in all the three countries was 2-3:1, and relapsing-remitting MS (RRMS) was the most frequent in all three countries. Vision loss was slow and progressive in half of the patients from the three countries, with no significant differences (p = 0.524). A higher percentage of steroid treatment was observed in Chinese patients in comparison with the patients from other two countries (p < 0.001), and a similar trend was seen in the use of traditional medicines. Almost one-third of patients who did not receive any treatment recovered spontaneously in all the three countries (p = 0.097). CONCLUSIONS: MS occurs more frequently in the relapsing-remitting clinical form and there is a clear female predominance. The first ocular crisis or clinical debut of MS is characterized by slow and progressive visual impairment, increasing and adding to other ocular manifestations during its evolutionary course. Spontaneous recovery of vision after an attack of optic neuritis in the course of MS is possible.

LncRNA OIP5-AS1 upregulates snail expression by sponging miR-34a to promote ovarian carcinoma cell invasion and migration.

BACKGROUND: Although OIP5-AS1 has been characterized as an oncogenic lncRNA in many types of cancer, its role and underlying mechanism in ovarian carcinoma (OC) remains unknown. This study aimed to investigate the role of OIP5-AS1 in OC. METHODS: OC tissues and non-tumor tissues (ovary tissues within 3 cm around tumors) were collected from 58 OC patients (age range 36 to 67 years old, mean age 51.4 ± 5.9 years old). The expression of OIP5-AS1 and snail in paired tissues were determined by RT-qPCR. The interaction between OIP5-AS1 and miR-34a was predicted by IntaRNA2.0 and confirmed by dual luciferase reporter assay. The effects of overexpression of OIP5-AS1 and miR-34a on the expression of snail were analyzed by RT-qPCR and Western blotting. Cell invasion and migration were analyzed by Transwell assay. RESULTS: We observed that the expression of OIP5-AS1 and snail was upregulated and positively correlated with each other in OC. RNA-RNA interaction analysis showed that OIP5-AS1 might sponge miR-34a. In OC cells, overexpression of OIP5-AS1 resulted in the upregulated expression of snail, while overexpression of miR-34a downregulated the expression of snail. In addition, overexpression of miR-34a reduced the effects of overexpression of OIP5-AS1 on the expression of snail. In cell invasion and migration assay, overexpression of OIP5-AS1 and snail resulted in increased OC cell invasion and migration, while overexpression of miR-34a decreased OC cell invasion and migration. Moreover, overexpression of miR-34a attenuated the effects of OIP5-AS1 overexpression on OC cell invasion and migration. CONCLUSIONS: Therefore, OIP5-AS1 may upregulate snail expression in OC by sponging miR-34a to promote OC cell invasion and migration.

Association between bile acid metabolism and bone mineral density in postmenopausal women.

OBJECTIVES: Previous studies have not shown any correlation between bile acid metabolism and bone mineral density (BMD) in women with postmenopausal osteoporosis. Thus, the current study evaluated the association between bile acid levels as well as BMD and bone turnover marker levels in this group of women. METHODS: This single-center cross-sectional study included 150 postmenopausal Chinese women. According to BMD, the participants were divided into three groups: osteoporosis group, osteopenia group, and healthy control group. Serum bile acid, fibroblast growth factor 19 (FGF19), and bone turnover biomarker levels were assessed. Moreover, the concentrations of parathyroid hormone, 25-hydroxy vitamin D [25(OH)D], procollagen type I N-peptide (P1NP), and beta-CrossLaps of type I collagen containing cross-linked C-terminal telopeptide (ß-CTX) were evaluated. The BMD of the lumbar spine and proximal femur were examined via dual-energy X-ray absorptiometry. RESULTS: The serum total bile acid levels in the osteoporosis and osteopenia groups (5.28±1.56 and 5.31±1.56 umol/L, respectively) were significantly lower than that in the healthy control group (6.33±2.04 umol/L; p=0.002 and 0.018, respectively). Serum bile acid level was positively associated with the BMD of the lumbar spine, femoral neck, and total hip. However, it negatively correlated with ß-CTX concentration. Moreover, no correlation was observed between bile acid and P1NP levels, and the levels of the other biomarkers that were measured did not differ between the groups. CONCLUSION: Serum bile acid was positively correlated with BMD and negatively correlated with bone turnover biomarkers reflecting bone absorption in postmenopausal women. Thus, bile acid may play an important role in bone metabolism.

Association between bile acid metabolism and bone mineral density in postmenopausal women

OBJECTIVES: Previous studies have not shown any correlation between bile acid metabolism and bone mineral density (BMD) in women with postmenopausal osteoporosis. Thus, the current study evaluated the association between bile acid levels as well as BMD and bone turnover marker levels in this group of women. METHODS: This single-center cross-sectional study included 150 postmenopausal Chinese women. According to BMD, the participants were divided into three groups: osteoporosis group, osteopenia group, and healthy control group. Serum bile acid, fibroblast growth factor 19 (FGF19), and bone turnover biomarker levels were assessed. Moreover, the concentrations of parathyroid hormone, 25-hydroxy vitamin D [25(OH)D], procollagen type I N-peptide (P1NP), and beta-CrossLaps of type I collagen containing cross-linked C-terminal telopeptide (β-CTX) were evaluated. The BMD of the lumbar spine and proximal femur were examined via dual-energy X-ray absorptiometry. RESULTS: The serum total bile acid levels in the osteoporosis and osteopenia groups (5.28±1.56 and 5.31±1.56 umol/L, respectively) were significantly lower than that in the healthy control group (6.33±2.04 umol/L; p=0.002 and 0.018, respectively). Serum bile acid level was positively associated with the BMD of the lumbar spine, femoral neck, and total hip. However, it negatively correlated with β-CTX concentration. Moreover, no correlation was observed between bile acid and P1NP levels, and the levels of the other biomarkers that were measured did not differ between the groups. CONCLUSION: Serum bile acid was positively correlated with BMD and negatively correlated with bone turnover biomarkers reflecting bone absorption in postmenopausal women. Thus, bile acid may play an important role in bone metabolism.

LncRNA OIP5-AS1 upregulates snail expression by sponging miR-34a to promote ovarian carcinoma cell invasion and migration

BACKGROUND: Although OIP5-AS1 has been characterized as an oncogenic lncRNA in many types of cancer, its role and underlying mechanism in ovarian carcinoma (OC) remains unknown. This study aimed to investigate the role of OIP5-AS1 in OC. METHODS: OC tissues and non-tumor tissues (ovary tissues within 3 cm around tumors) were collected from 58 OC patients (age range 36 to 67 years old, mean age 51.4 ± 5.9 years old). The expression of OIP5-AS1 and snail in paired tissues were determined by RT-qPCR. The interaction between OIP5-AS1 and miR-34a was predicted by IntaRNA2.0 and confirmed by dual luciferase reporter assay. The effects of overexpression of OIP5-AS1 and miR-34a on the expression of snail were analyzed by RT-qPCR and Western blotting. Cell invasion and migration were analyzed by Transwell assay. RESULTS: We observed that the expression of OIP5-AS1 and snail was upregulated and positively correlated with each other in OC. RNA-RNA interaction analysis showed that OIP5-AS1 might sponge miR-34a. In OC cells, overexpression of OIP5-AS1 resulted in the upregulated expression of snail, while overexpression of miR-34a downregulated the expression of snail. In addition, overexpression of miR-34a reduced the effects of overexpression of OIP5-AS1 on the expression of snail. In cell invasion and migration assay, overexpression of OIP5-AS1 and snail resulted in increased OC cell invasion and migration, while overexpression of miR-34a decreased OC cell invasion and migration. Moreover, overexpression of miR-34a attenuated the effects of OIP5-AS1 overexpression on OC cell invasion and migration. CONCLUSIONS: Therefore, OIP5-AS1 may upregulate snail expression in OC by sponging miR-34a to promote OC cell invasion and migration.

Households characteristics and perceptions of weather variability impact on rice yield: empirical analysis of small scale farmers in Tanzania / Características dos agregados familiares e percepções da variabilidade climática na produção de arroz: análise empírica de pequenos agricultores na Tanzânia

Rice farming is characterized by various factors including environmental and non-environmental factors. The current paper analyses the influence of households characteristics, and perceptions of weather variability on rice yield. Authors used primary data collected from small-scale rice farmers in the Mbeya region of Tanzania. Garret technique and Stata software were used for data analyses. Results confirmed that farmers education, marital status, gender, and land ownership have a positive influence on rice yield. Thus, for every 1% increase in each variable increases rice yield by 14%, 98%, 26%, and 21% respectively. Owing to empirical results on farmers perceptions, it is confirmed that if the drought period increased by 1%, would on average reduce rice yield by 20%. The majority of farmers (70%) have perceived that drought period reduced their rice yield. In addition, farmers used averagely less quantity of rice seeds which have impaired their rice yields. If farmers increased the seed quantity by 1%, rice yields would increase by 17%. Our findings also revealed that the previous market price has positive association with the next seasons rice yield. Therefore, our study concluded that among households variables and their perceptions have positive implications on rice yield; however, with the empirical analyses other variables were insignificant due to multicollinearity effects. Authors recommended to the government and other responsible organizations to capitalize on irrigation infrastructures, agricultural extension and technological services to restraint the enduring food insecurity coercions in Tanzania.(AU)

O presente trabalho analisa a influência das características das famílias e as percepções da variabilidade climática na produção de arroz. Os autores usaram dados primários coletados de pequenos produtores de arroz na região de Mbeya, na Tanzânia. A técnica de Garret e o software Stata foram utilizados para análise de dados. Os resultados confirmam que a educação do agricultor, estado civil, gênero e propriedade da terra têm uma influência positiva no rendimento do arroz. Assim, para cada aumento de 1% em cada variável aumenta a produção de arroz em 14%, 98%, 26% e 21%, respectivamente. Devido aos resultados empíricos sobre as percepções dos agricultores confirma-se que se o período de seca aumentar 1%, reduziria em média a produção de arroz em 20%. A maioria dos agricultores (70%) percebeu o período de seca para reduzir o rendimento do arroz. Além disso, os agricultores usam uma quantidade média menor de sementes de arroz que prejudicaram o rendimento do arroz. Se os agricultores aumentarem a quantidade de sementes em 1%, o rendimento do arroz aumentará em 17%. Nossas descobertas também revelaram que o preço de mercado anterior tem associação positiva com a produção de arroz das próximas safras. Portanto, nosso estudo conclui que entre as variáveis das famílias e suas percepções apresentam uma implicação positiva na produção de arroz, no entanto, com as análises empíricas, outras variáveis foram insignificantes devido aos efeitos de multicolinearidade. Os autores recomendaram ao governo e a outras organizações responsáveis que capitalizassem as infraestruturas de irrigação, a extensão agrícola e os serviços tecnológicos para conter as coercões duradouras de insegurança alimentar na Tanzânia.(AU)

Households' characteristics and perceptions of weather variability impact on rice yield: empirical analysis of small scale farmers in Tanzania / Características dos agregados familiares e percepções da variabilidade climática na produção de arroz: análise empírica de pequenos agricultores na Tanzânia

ABSTRACT: Rice farming is characterized by various factors including environmental and non-environmental factors. The current paper analyses the influence of households' characteristics, and perceptions of weather variability on rice yield. Authors used primary data collected from small-scale rice farmers in the Mbeya region of Tanzania. Garret technique and Stata software were used for data analyses. Results confirmed that farmer's education, marital status, gender, and land ownership have a positive influence on rice yield. Thus, for every 1% increase in each variable increases rice yield by 14%, 98%, 26%, and 21% respectively. Owing to empirical results on farmers' perceptions, it is confirmed that if the drought period increased by 1%, would on average reduce rice yield by 20%. The majority of farmers (70%) have perceived that drought period reduced their rice yield. In addition, farmers' used averagely less quantity of rice seeds which have impaired their rice yields. If farmers increased the seed quantity by 1%, rice yields would increase by 17%. Our findings also revealed that the previous market price has positive association with the next seasons' rice yield. Therefore, our study concluded that among households' variables and their perceptions have positive implications on rice yield; however, with the empirical analyses other variables were insignificant due to multicollinearity effects. Authors recommended to the government and other responsible organizations to capitalize on irrigation infrastructures, agricultural extension and technological services to restraint the enduring food insecurity coercions in Tanzania.

RESUMO: O presente trabalho analisa a influência das características das famílias e as percepções da variabilidade climática na produção de arroz. Os autores usaram dados primários coletados de pequenos produtores de arroz na região de Mbeya, na Tanzânia. A técnica de Garret e o software Stata foram utilizados para análise de dados. Os resultados confirmam que a educação do agricultor, estado civil, gênero e propriedade da terra têm uma influência positiva no rendimento do arroz. Assim, para cada aumento de 1% em cada variável aumenta a produção de arroz em 14%, 98%, 26% e 21%, respectivamente. Devido aos resultados empíricos sobre as percepções dos agricultores confirma-se que se o período de seca aumentar 1%, reduziria em média a produção de arroz em 20%. A maioria dos agricultores (70%) percebeu o período de seca para reduzir o rendimento do arroz. Além disso, os agricultores usam uma quantidade média menor de sementes de arroz que prejudicaram o rendimento do arroz. Se os agricultores aumentarem a quantidade de sementes em 1%, o rendimento do arroz aumentará em 17%. Nossas descobertas também revelaram que o preço de mercado anterior tem associação positiva com a produção de arroz das próximas safras. Portanto, nosso estudo conclui que entre as variáveis das famílias e suas percepções apresentam uma implicação positiva na produção de arroz, no entanto, com as análises empíricas, outras variáveis foram insignificantes devido aos efeitos de multicolinearidade. Os autores recomendaram ao governo e a outras organizações responsáveis que capitalizassem as infraestruturas de irrigação, a extensão agrícola e os serviços tecnológicos para conter as coercões duradouras de insegurança alimentar na Tanzânia.

Expressions of TOLL-like receptor 4 (TLR-4) and matrix metalloproteinase 9 (MMP-9)/Tissue inhibitor of metalloproteinase 1 (TIMP-1) in pulmonary blood vessels with chronic obstructive pulmonary diseases and their relationships with pulmonary vascular remodelling.

OBJECTIVE: This study aims at investigating the expressions of TOLL-like receptor 4 (TLR-4) and matrix metalloproteinase 9 (MMP-9)/ tissue inhibitor of metalloproteinase 1 (TIMP-1) in pulmonary blood vessels with chronic obstructive pulmonary disease (COPD) and their relationships with pulmonary vascular remodelling (PVR). METHODS: 60 para-tumour tissues were divided into the COPD group and the control group (n=30); the inflammations, pulmonary artery wall area/total artery area (WA%), and wall thickness/vascular outer diameter (WT%) were compared. The expressions of TLR-4, MMP-9/TIMP-1, and PCNA in pulmonary vascular smooth muscle cells were detected, and their relationships with PVR were then analysed. RESULTS: The inflammations (1.6±0.8), WA% (44.0±6.4), and WT% (27.3±3.3) in the COPD group were higher than in the control group (0.3±0.5, 26.1±2.8, 15.6±1.8), and the expressions of TLR-4 (31.4±147) and MMP-9/TIMP-1 (2.2±2.6) were increased compared to the control group (4.7±4.5, 1.9±12). Correlation analysis: TLR-4 and MMP-9/TIMP-1 were positively correlated with the inflammations (r=0.18, P<0.01), WA% (r=0.68, P<0.01), and WT% (r=0.73, P<0.01), as well as positively correlated with the expression of PCNA (r=0.44, P<0.01); the upregulation of TLR-4 was positively correlated with the expressions of MMP-9 and TIMP-1. CONCLUSIONS: The upregulation of TLR-4 in the pulmonary arterial smooth muscle cells of COPD patients could promote the inflammations and the MMP-9 expression, thus causing abnormal degradation of extracellular matrix, so it played an important role in the process of PVR.

Expressions of TOLL-like receptor 4 (TLR-4) and matrix metalloproteinase 9 (MMP-9)/Tissue inhibitor of metalloproteinase 1 (TIMP-1) in pulmonary blood vessels with chronic obstructive pulmonary diseases and their relationships with pulmonary vascular remodelling

SUMMARY OBJECTIVE: This study aims at investigating the expressions of TOLL-like receptor 4 (TLR-4) and matrix metalloproteinase 9 (MMP-9)/ tissue inhibitor of metalloproteinase 1 (TIMP-1) in pulmonary blood vessels with chronic obstructive pulmonary disease (COPD) and their relationships with pulmonary vascular remodelling (PVR). METHODS: 60 para-tumour tissues were divided into the COPD group and the control group (n=30); the inflammations, pulmonary artery wall area/total artery area (WA%), and wall thickness/vascular outer diameter (WT%) were compared. The expressions of TLR-4, MMP-9/TIMP-1, and PCNA in pulmonary vascular smooth muscle cells were detected, and their relationships with PVR were then analysed. RESULTS: The inflammations (1.6±0.8), WA% (44.0±6.4), and WT% (27.3±3.3) in the COPD group were higher than in the control group (0.3±0.5, 26.1±2.8, 15.6±1.8), and the expressions of TLR-4 (31.4±147) and MMP-9/TIMP-1 (2.2±2.6) were increased compared to the control group (4.7±4.5, 1.9±12). Correlation analysis: TLR-4 and MMP-9/TIMP-1 were positively correlated with the inflammations (r=0.18, P<0.01), WA% (r=0.68, P<0.01), and WT% (r=0.73, P<0.01), as well as positively correlated with the expression of PCNA (r=0.44, P<0.01); the upregulation of TLR-4 was positively correlated with the expressions of MMP-9 and TIMP-1. CONCLUSIONS: The upregulation of TLR-4 in the pulmonary arterial smooth muscle cells of COPD patients could promote the inflammations and the MMP-9 expression, thus causing abnormal degradation of extracellular matrix, so it played an important role in the process of PVR.

RESUMO OBJETIVO: Este estudo tem como objetivo investigar as expressões de TOLL-like receptor 4 (TLR-4) e metaloproteinase 9 da matriz (MMP-9)/inibidor de tecido da metaloproteinase 1 (TIMP-1) em vasos sanguíneos pulmonares com doença pulmonar obstrutiva crônica (DPOC) e suas relações com o remodelamento vascular pulmonar (PVR). MÉTODOS: Sessenta tecidos paratumorais foram divididos em grupo COPD e o grupo controle (n = 30). Foram comparadas as inflamações, área da parede da artéria pulmonar/área da artéria total (WA%) e espessura da parede/diâmetro externo vascular (WT%). As expressões de TLR-4, MMP-9/TIMP-1 e PCNA em células de músculo liso vascular pulmonar foram detectadas, e suas relações com PVR foram então analisadas. RESULTADOS: As inflamações (1,6 ± 0,8), WA% (44,0 ± 6,4) e WT% (27,3 ± 3,3) no grupo COPD foram maiores que no grupo controle (0,3 ± 0,5; 26,1 ± 2,8; 15,6 ± 1,8). E as expressões de TLR-4 (31,4 ± 14,7) e MMP-9/TIMP-1 (2,2 ± 2,6) foram aumentadas em relação ao grupo controle (4,7 ± 4,5, 1,9 ± 1,2). Na análise de correlação, TLR-4 e MMP-9/TIMP-1 foram positivamente correlacionadas com as inflamações (r = 0,18; P <0,01), WA% (r = 0,68; P <0,01) e WT% (r = 0,73; P <0,01), bem como correlacionadas positivamente com a expressão de PCNA (r = 0,44; P <0,01). A elevação da TLR-4 foi correlacionada positivamente com as expressões de MMP-9 e TIMP-1. CONCLUSÕES: A regulação positiva do TLR-4 nas células do músculo liso arterial pulmonar de pacientes com DPOC poderia promover as inflamações e a expressão de MMP-9, causando assim uma degradação anormal da matriz extracelular, por isso desempenhou um papel importante no processo de PVR.

Risk of cancer in children, adolescents, and young adults with autistic disorder.

OBJECTIVES: To investigate whether individuals with autism have an increased risk for cancer relative to the general population. STUDY DESIGN: We enrolled patients with autistic disorder from the Taiwan National Health Insurance database in years 1997-2011. A total of 8438 patients diagnosed with autism were retrieved from the Registry for Catastrophic Illness Patients database. The diagnosis of cancers was also based on the certificate of catastrophic illness, which requires histological confirmation. The risk of cancer among the autism cohort was determined with a standardized incidence ratio (SIR). RESULTS: During the observation period, cancer occurred in 20 individuals with autism, which was significantly higher than a total number of expected cancers with a SIR estimate of 1.94 (95% CI 1.18-2.99). The number of cancer in males was greater than the expected number with a SIR of 1.95 (1.11-3.16), but no excess risk was found for females with a SIR of 1.91 (0.52-4.88). Cancer developed more than expected in individuals age 15-19 years with the SIR of 3.58 (1.44-7.38), but did not differ in other age range groups. The number of cancers of genitourinary system was significantly in excess of the expected number (SIR 4.15; 95% CI 1.13-10.65), and increased risk was found in ovarian cancer with SIR of 9.21 (1.12-33.29). CONCLUSIONS: Our study demonstrated that patients with autistic disorder have an increased risk of cancer.

Density interactions among Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus in the nasopharynx of young Peruvian children.

Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus are commonly carried in the nasopharynx of young children, and have been speculated to interact with each other. Although earlier studies used cultures alone to assess these interactions, the addition of real-time quantitative polymerase chain reaction (qPCR) provides further insight into these interactions. We compared results of culture and qPCR for the detection of these 3 bacteria in 446 nasopharynx samples collected from 360 healthy young children in a prospective cohort study in the Peruvian Andes. Patterns of concurrent bacterial colonization were studied using repeated measures logistic regression models with generalized estimating equations. Spearman correlation coefficients were used to assess correlations among bacterial densities. At a bacterial density <10 colony forming units/mL measured by qPCR, culture detected significantly less carriers (P < 0.0001) for all 3 pathogens, than at a bacterial density >10 colony forming units/mL. In addition, there was a positive association between S. pneumoniae and H. influenzae colonization measured by both culture (odds ratio [OR] 3.11-3.17, P < 0.001) and qPCR (OR 1.95-1.97, P < 0.01). The densities of S. pneumoniae and H. influenzae, measured by qPCR, were positively correlated (correlation coefficient 0.32, P < 0.001). A negative association was found between the presence of S. pneumoniae and Staphylococcus aureus in carriage with both culture (OR 0.45, P = 0.024) and qPCR (OR 0.61, P < 0.05). The impact of density on detection by culture and the observed density-related interactions support use of qPCR in additional studies to examine vaccine effects on diverse bacterial species.

Heme oxygenase-1 mediates the inhibitory actions of brazilin in RAW264.7 macrophages stimulated with lipopolysaccharide.

Brazilin, the main constituent of Caesalpinia sappan L., is a natural red pigment that has been reported to possess anti-inflammatory properties. This study aimed to identify a novel anti-inflammatory mechanism of brazilin. We found that brazilin did not cause cytotoxicity below 300 microM, and activated heme oxygenase-1 (HO-1) protein synthesis in a concentration-dependent manner at 10-300 microM in RAW264.7 macrophages without affecting mRNA transcription of HO-1. Additionally, brazilin increased bilirubin production and HO-1 activity in RAW264.7 macrophages. In lipopolysaccharide (LPS)-stimulated macrophages, brazilin suppressed the release of nitric oxide (NO), prostaglandin E(2) (PGE(2)), interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha), and reduced the expression of inducible nitric oxide synthase (iNOS). A specific inhibitor of HO-1, Zn(II) protoporphyrin IX, blocked the suppression of NO production, cytokines release and iNOS expression by brazilin. These results suggest that brazilin possesses anti-inflammatory actions in macrophages and works through a novel mechanism involving the action of HO-1.

Induction of vasorelaxation through activation of nitric oxide synthase in endothelial cells by brazilin.

The vasorelaxant activity of Caesalpinia sappan L., a traditional Chinese medicine, and its major component brazilin were investigated in isolated rat aorta and human umbilical vein endothelial cells. In isolated rat aorta, C. sappan L. extract and brazilin relaxed phenylephrine-induced vasocontraction and increased cyclic guanosine 3',5'-monophosphate (cGMP) content. Induction of vasorelaxation of brazilin was endothelium-dependent and could be markedly blocked by pretreatment with nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME); N(G)-monomethyl-L-arginine acetate (L-NMMA) and guanylyl cyclase inhibitor, methylene blue; 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and nitric oxide (NO) scavenger, hemoglobin. The increasing cGMP content induced by brazilin was also blocked by pretreatment with L-NAME, methylene blue, and the removal of extracellular Ca(2+). In human umbilical vein endothelial cells, brazilin dose-dependently induced an increase in NO formation and NOS activity, which were greatly attenuated by either the removal of extracellular Ca(2+) or the chelating of intracellular Ca(2+) chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM). Moreover, brazilin dose-dependently induced the influx of extracellular Ca(2+) in human umbilical vein endothelial cells. Collectively, these results suggest that brazilin induces vasorelaxation by the increasing intracellular Ca(2+) concentration in endothelial cells of blood vessels and hence activating Ca(2+)/calmodulin-dependent NO synthesis. The NO is released and then transferred into smooth muscle cells to activate guanylyl cyclase and increase cGMP content, resulting in vasorelaxation.

The role of plasminogen activator receptor in cancer invasion and dormancy

Urokinase plasminogen activator receptor (uPAR) has been identified some 15 years ago and the anticipation was that is presence on the cell surface will provide a focus for anchoring uPA and possibly protect the enzyme from native inhibitors. The studies of the last decade have shown that uPA localized to the surface of cells by uPAR is indeed an important factor in the process of cancer cell invasion and metastasis. We developed a chick embryo model in which we showed that uPAR is crucial in invasion of stroma and in intravasation (breaching of the blood vessels walls). More recently and unexpectedly, uPAR-a protein anchored in the outer leaflet of the plasma membrane, has been shown to initiate signal transduction events and affect cell migration. We have shown that uPAR co-associates with fibronectin binding integrin, alpha5beta1, activates them and that this interaction leads to a greatly increased level of active ERK. When the association between uPAR and integrin or integrin and fibronectin are interrupted either by reduction of surface uPAR expression, or by other means, human carcinoma cells enter a state of protracted dormancy. We show that very high levels of active ERK are required to keep cancer cells proliferating in vivo. (AU)

The role of plasminogen activator receptor in cancer invasion and dormancy

Urokinase plasminogen activator receptor (uPAR) has been identified some 15 years ago and the anticipation was that is presence on the cell surface will provide a focus for anchoring uPA and possibly protect the enzyme from native inhibitors. The studies of the last decade have shown that uPA localized to the surface of cells by uPAR is indeed an important factor in the process of cancer cell invasion and metastasis. We developed a chick embryo model in which we showed that uPAR is crucial in invasion of stroma and in intravasation (breaching of the blood vessels walls). More recently and unexpectedly, uPAR-a protein anchored in the outer leaflet of the plasma membrane, has been shown to initiate signal transduction events and affect cell migration. We have shown that uPAR co-associates with fibronectin binding integrin, alpha5beta1, activates them and that this interaction leads to a greatly increased level of active ERK. When the association between uPAR and integrin or integrin and fibronectin are interrupted either by reduction of surface uPAR expression, or by other means, human carcinoma cells enter a state of protracted dormancy. We show that very high levels of active ERK are required to keep cancer cells proliferating in vivo.

The role of nitric oxide (NO) in control of hypothalamic-pituitary function

Neurons containing neural nitric oxide synthase (nNOS) are found in various locations in the hypothalamus and, in particular, in the paraventricular and supraoptic nuclei with axons which project to the median eminence and extend into the neural lobe where the highest concentrations of NOS are found in the rat. Furthermore, nNOS is also located in folliculostellate cells and LH gonadotropes in the anterior pituitary gland. To define the role of NO in the release of hypothalamic peptides and pituitary hormones, we inected an inhibitor of NOS, Ng- monomethyl-L-arginine (NMMA) or a releasor of NO, nitroprusside (NP) into the third ventricle (3V) of conscious castrate rats and determined the effect on the release of various pituitary hormones. In vitro, we incubated medial basal hypothalamic (MBH) fragments and studied inhibitors of NO synthase and also releasors of NO. The results indicate that NOergic neurons play an important role in stimulating the release of corticotrophin-releasing hormone (CRH), luteinizing hormone releasing-hormone (LHRH), prolactin-RH's, particularly oxytocin, growth hormone-RH (GHRH) and somatostatin, but not FSH-releasing factor from the hypothalamus. NO stimulates the release of LHRH, which induces sexual behavior, and causes release of LH from the pituitary gland. The intrahypothalamic pathway by which NO controls LHRH release is as follows: glutamergic neurons synapse with noradrenergic terminals in the MBH which release nonepinephrine (NE) that acts on alpha1 receptors on the NOergic neuron to increase intracellular free Ca++ which combines with calmodulin to activate NOS. The NOS diffuses to the LHRH terminal and activates guanylate cyclase (GC), cyclooxygenase and lipoxygenase causing release of LHRH via release of cyclic GMP, PGE2 and leukotrienes, respectively. Alcohol and cytokines can block LHRH release by blocking the activation of cyclooxygenase and lipoxygenase without interfering with the activation of GC. GABA also blocks the response of the LHRH neurons to NO and recent experiments indicate that granulocyte macrophage colony-stimulating factor (GMCSF) blocks the response of the LHRH neuron to NP by activation of GABA neurons since the blockase can be reversed by the competitive inhibitor of GABAa receptors, bicuculine.